POLYPHARMACY AND POLYPRAGMASY IN CARDIOVASCULAR ELDERLY PATIENTS

POLYPHARMACY AND POLYPRAGMASY IN CARDIOVASCULAR ELDERLY PATIENTS Prof. Daniel Pella, MD, PhD. 1st Dept. of Medicine P. J. Safarik University and L. Pasteur University Hospital Košice Slovakia 2nd CPPEI, Vienna, July 07-09, 2017

POLYPHARMACY Concomitant use of at least two drugs (in some definitions at least 4-5 drugs) Evidence based polypharmacy very common in treatment of many CV diseases Trend towards use of FDC (fixed drug combinations) Concept of polypill

POLYPRAGMASY Too many drugs administered to the patient at the same time concurrent (or more) therapeutic approaches at the same time Prolonged use of drugs or in uncorrect dosages (usually higher) Both terms polypharmacy and polypragmasy are quite commonly wrongly interpreted by physicians In majority of cases polypragmasy represent not recommended and not-effective therapy

CLASSES OF RECOMMENDATION Class I Class II a Class II b Class III Evidences and common agreement about benefits and efficacy Not clear evidence, different opinions (benefits vs. efficacy), but in general positive opinion prevails Benefit and efficacy less confirmed by evidences or opinions Evidence or consensus treatment is not beneficial, not effective, or may be even harmful

LEVELS OF EVIDENCE Level of evidence A Level of evidence B Level of evidence C More randomized clinical trials or meta-analyses One randomized clinical trial or large non-randomized trials Experts opinions consensus or small trials, retrospective studies, registries

WHY IS POLYPHARMACY SO PREVALENT? Once drug is indicated and not prescribed who will protect doctor? (Medical chambers? Professional organizations? Lawyers? Patients? Media?) guidelines - clearly written, but... (use of personalized medicine is possibly better like EBM results from clinical studies where pts. are selected by inclusion and exclusion criteria real life patient is usually different comorbidities, other treatment, etc.)

WHY IS POLYPHARMACY SO PREVALENT? E-Health not yet available in all countries doctors are not properly informed about each other prescriptions (double prescriptions from the same class of drugs, physicians are not aware about possible interactions) Patient requests some drug I am aware I need this one (no prescription after examination of patient bad doctor - did not find something wrong, would like to save money for insurance company, etc.)

THE MOST COMMON CV DISEASE IN ELDERLY PATIENTS Arterial hypertension Atherosclerosis and its equivalents (all forms and locations, mainly coronary and cerebral circulation) Heart failure (both acute and chronic most frequent acute worsening of chronic heart failure) Dyslipidemia

ARTERIAL HYPERTENSION Prevalence is increasing with age, in elderly population more than 50 % Diastolic hypertension typical for younger individuals (or systolic-diastolic one), in the elderly mostly prevalent is isolated systolic hypertension Majority of HT subjects require for HT control at least two antihypertensives (in elderly preferred low doses more active substances fixed dose combinations, single pill)

Aged under 55 years A Aged over 55 years or black person of African or Caribbean family origin of any age C 2 Step 1 Summary of antihypertensive drug treatment A + C 2 A + C + D Resistant hypertension A + C + D + consider further diuretic 3, 4 or alpha- or beta-blocker 5 Consider seeking expert advice Step 2 Step 3 Step 4 Key A ACE inhibitor or low-cost angiotensin II receptor blocker (ARB) 1 C Calcium-channel blocker (CCB) D Thiazide-like diuretic NICE Guidelines Hypertension, 2011

OPTIMIZING THERAPY OF HYPERTENSIVE PATIENTS WITH HYPERTENSION AND/OR CAD USING FIXED COMBINATION OF PERINDOPRIL ARGININE/AMLODIPINE 2009-2011 Hatala R, Pella D, Hatalová K, et al. Clin Drug Investig 2012

Demography BASELINE CHARACTERISTICS 9658 pts. Women (48%) Men (52%) Age 60,7 years 63,3 years 58,4 years Height 170,4 cm 164,1 cm 176,2 cm Weight 85,0 kg 79,1 kg 90,4 kg waist 97,3 cm 93,8 cm 100,5 cm BMI* 29,3 29,4 29,2 Arterial hypertension SBP (mmhg) DBP (mmhg) HR (rate/min) 158,0 158,6 157,4 94,6 94,1 95,0 74,8 75,1 74,6 *Overweight (BMI >25 kg /m 2 ) Hatala R, Pella D, Hatalová K, et al. Clin Drug Investig 2012

HYPERTENSION AND CAD THERAPY - BASELINE (25% PATIENTS WITH CAD) 9658 patients % ACE inhibítors 63 Calcium channel blockers 52 Betablockers 35 Diuretics 21 AT1 receptor blockers (sartans) 6 Central acting antihypertensives 15 Antithrombotic treatment 30 Lipid lowering drugs 34 Other coronary therapy* 11 Nitrates 7 Data on file * trimetazidine, ivabradine, molsidomíne Hatala R, Pella D, Hatalová K, et al. Clin Drug Investig 2012

COMBINED ANTIHYPERTENSIVE TREATMENT THE ONLY WAY HOW TO ACHIEVE TARGET BP LEVELS Study (final SBP) ASCOT-BPLA (136,9 mmhg) ALLHAT (138 mmhg) IDNT (138 mmhg) RENAAL (141 mmhg) UKPDS (144 mmhg) ABCD (132 mmhg) MDRD (132 mmhg) HOT (138 mmhg) AASK (128 mmhg) 1 2 3 4 Bakris et al. Am J Med 2004;116(5A):30S 8 Dahlöf et al. Lancet 2005;366:895 906 The average number of antihypertensive agents needed

WHAT WE HAVE SHOWN IN SYMBIO TRIAL? - Hypertensive patients are usually treated according guidelines, majority of them with ACE-inhibitors and CCB, or even more antihypertensives were used - Despite this fact not achieving treatment goals (BP below 140/90 mm Hg) Hatala R, Pella D, Hatalová K, et al. Clin Drug Investig 2012

DECREASE OF BLOOD PRESSURE CHANGE FROM USUAL CARE TO PERINDOPRIL ARGININE + AMLODIPINE 158 141 133 94 84 81 Hatala R, Pella D, Hatalova K, et al. Clin Drug Investig 2012; 32 (9): 603-612.

SYMBIO TRIAL CONCLUSIONS I. - All previously prescribed ACE-inhibitors and CCB were changed to perindopril arginine and amlodipine administered in combination (not FDC) - This change led to additional significant decrease of BP Hatala R, Pella D, Hatalová K, et al. Clin Drug Investig 2012

SYMBIO TRIAL CONCLUSIONS II. - In the subsequent study we just changed free combination of perindopril arginine and amlodipine to fixed dose combination (FDC) - Surprisingly (? or not...) this change led to next additional significant decrease of BP Hatala R, Pella D, Hatalová K, et al. Clin Drug Investig 2012

THE SAME DOSAGE COHORT OF PTS. CHANGE FROM FREE COMBINATION TO FDC time (in months) Hatalova K, Pella D, Hatala R, et al. Clin Drug Investig 2012

SYMBIO TRIAL WHAT WE HAVE LEARNED? - One explanation better adherence (compliance) when administered in one tablet daily - Drugs could be effective only if patients are taking them... - There are moreover some other benefits of such FDC described (better availability, absorption, etc.) Hatala R, Pella D, Hatalová K, et al. Clin Drug Investig 2012

PARALLELS IN TREATMENT APPROACH ARTERIAL HYPERTENSION AND DYSLIPIDEMIA JNC I diuretics, subsequent dose titration JNC II-IV betablockers, CCB, ACE-inhibitors JNC V prefered high doses in monotherapy JNC VI possibly combined treatment like the first step in treatment ATP I target LDL-C levels 3,4 mmol/l resp. 4,1 mmol/l, the first choice - niacin and bile acid sequestrants, statins only exceptionally ATP II target LDL-C levels 2,6 mmol/l, resp. 3,4mmol/l - recommended statiny, niacin, bile acid sequestrants, fibrates ATP III complete dominance of statins, target level of LDL-C below 2,6mmol/l JNC VII combined treatment even in newly diagnosed arterial hypertension Addendum ATP III target level of LDL-C below 1,8 mmol/l??? combined treatment for majority of very high risk or high risk patients

MAJORITY OF VERY HIGH RISK AND HIGH RISK PTS.DID NOT REACH LDL-C TARGET <2,5 MMOL/L (<1,8 MMOL/L) 1 Pts. not at target LDL-C <2,5 mmol/l 49% 56% Pacienti dosahujúci cieľové hodnoty LDL-C, % a 100 80 60 40 20 0 44% 11% LDL-C < 2,5 mmol/l 47% 13% 50% 16% LDL-C <1,8 mmol/l 49% 15% 51% 16% 2004 2005 2006 2007 2008 (Jan Aug) N=178,027 N=220,084 N=227,517 N=166,497 N=168,790 Pts. not at target LDL-C <1,8 mmol/l 84% 89% a Study population defined as CHD or CHD-equivalent individuals (treated and untreated) identified by ICD-9 and CPT diagnosis and procedure codes. ICD-9 = International Classification of Diseases, ninth edition; CPT = Current Procedural Terminology. 1. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004.

Relative change * after 12 weeks HYBRID TREATMENT SIGNIFICANTLY LOWER BOTH, CHOLESTEROL ABSORPTION AND PRODUCTION 30 20 10 0 10 20 30 40 50 0.4 Placebo (n=62) 3 4 Statin 10 80 mg (n=232) 27 38 21 Ezetimib 10 mg + statin 10 80 mg (n=229) 38 22 25 total cholesterol cholesterol production cholesterol absorption *Ratio (sterol:tc)=mean(10 2 mmol/mol). Sterol=sitosterol (absorption) and lathosterol (production) Adapted from Assmann G et al. Poster presented at the American College of Cardiology, New Orleans, Louisiana, USA, March 7 10, 2004.

ATHEROGENIC LIPOPROTEINS PHENOTYPE AND ATHEROGENESIS - Increased triglycerides - Decreased HDL-C - Conglomerate of apolipoproteins B (mainly apo B100) - Increased apolipoprotein CIII (increased VLDL) - Increased small dense LDL-particles

MAY ADDING OF FENOFIBRATE TO STATIN THERAPY INCREASE ITS SAFETY? IN THE PAST WE LEARNED OPPOSITE...BUT Statins increase expression of PCSK9 This statin effect could be modified with fenofibrate by dual mechanisms (blocking of RNA expression of PCSK9 and increasing of expression of RNA furine, which inactivate protease PCSK9 PCSK9 activity correlates very well with increased BMI, increased TG and insulin rezistence - statins and risk of newly diagnosed DM type 2 may be decreased by adding of fenofibrate but......next tablet to be prescribed... Konrad JR, et al. Lipids Health Dis 2011

DYSLIPIDEMIA TREATMENT IN ELDERLY PATIENTS Elderly pts. mostly very high risk pts. (target of LDL<1,8 mmol/l at least hybrid therapy is needed 2 lipid lowering drugs ( statin +ezetimibe), possibly PCSK9 inhibitor Atherogenic lipoproteins phenotype - add fenofibrate (TG>2,3 mmol/l, HDL<0,9 mmol/l)??? The higher is the age the higher is risk of myopathy (arround 10-20% in elderly population) Risk may be dramatically increased with number of pills used (not only those of lipid lowering)

PHARMACOLOGICAL APPROACH CAD (STABLE ANGINA PECTORIS) Prognosis improvement Antithrombotic therapy Statins ACE inhibitors β-blockers Reduction or symptoms removal β-blockers, Long-acting nitrates Calcium channel blockers Metabolic treatment I f inhibitor - ivabradine

CHRONIC HEART FAILURE - EPIDEMIOLOGY Dramatically increasing at the age arround 75 years Prevalence 70-80- years old: 10-20% Heart Failure Malignant Disease!!! (mortality 2-times higher like in breast cancer or urine bladder, identical with colonic cancer) Remember: 10% of all hospitalized pts. due to acute or acute worsening of CHF

NUMBER OF PILLS USSUALLY PRESCRIBED IN CHF ACE-inhibitors perindopril enalapril lisinopril ramipril trandolapril Sartans (AT 1 receptor blockers) candesartan valsartan -blocker bisoprolol carvedilol metoprolol succinate nebivolol (seniors) Aldosteron antagonists eplerenone spironolaktone

Guidelines for CHF

Patient XY, born after 1952 hypertensive, diabetes type 2, combined dyslipidemia, history of CAD with stable angina pectoris- suddenly hospitalized for acute myocardial infarction with LV dysfunction Treatment at discharge: (in red tablets before hospitalization) atorvastatin 80 mg tbl., bisoprolol 5 mg tbl., perindopril arginine 10 mg tbl., indapamid 1,5 mg tbl. ASA 100mg tbl., clopidogrel 75 mg tbl., fenofibrate 160 mg tbl., rilmenidine 1 mg tbl., ivabradine 2x5 mg tbl., amlodipine 2x5mg tbl., gliclazide 80 mg 13...not too many tablets? All prescribed when cardiologists follow guidelines...

Patient XY, born after 1952 hypertensive, diabetes type 2, combined dyslipidemia, history of CAD with stable angina pectoris- suddenly hospitalized for acute myocardial infarction with LV dysfunction - Moreover patient is suffering from back pain sporadically - Chronic obstructive pulmonary disease - after 3 months still not on the target with LDL- C (familial dyslipidemia or poor compliance?) - BP borderline values... - how to proceed? Add ezetimibe? PCSK9? Next antihypertensive agent?

Patient XY, born after 1952 hypertensive, diabetes type 2, combined dyslipidemia, history of CAD with stable angina pectoris- suddenly hospitalized for acute myocardial infarction with LV dysfunction Treatment at discharge: (in red tablets before hospitalization) atorvastatin 80 mg tbl., bisoprolol 5 mg tbl., perindopril arginine 10 mg tbl., indapamid 1,5 mg tbl. ASA 100mg tbl., clopidogrel 75 mg tbl., fenofibrate 160 mg tbl., rilmenidine 1 mg tbl., ivabradine 2x5 mg tbl., amlodipine 2x5mg tbl., gliklazid 80 mg New treatment: from 13 tablets to 7 tablets and even morfe effective Implicor 2x50/5 mg, Triplixam 10/2,5/10, Atozet 80/10mg,ASA 100mg, Clopidogrel 75 mg, gliclazide 80 mg

INNOVATIVE TREATMENT FOR CAD, CHF AND DYSLIPIDEMIA MORE DRUGS TO BE USED? sacubitril and valsartan (?) Canakinumab (?) PCSK 9 inhibitors Other monoclonal antibodies

EDUCATION AND HEALTHY LIFESTYLE BACKGROUND FOR RATIONAL POLYPHARMACY Etiology, diagnosis, prognosis, compliance to therapy Symptoms monitoring, more applied self-care The way how to increase drug adherence FDC (based on EBM) Regular physical activity may lead to reduction of number of tablets needed

EDUCATION AND HEALTHY LIFESTYLE BACKGROUND FOR RATIONAL POLYPHARMACY Quit smoking, limited consumption of alcohol Relax, entertainment, physical activity (sexual as well) prevent depression Always remember words from Hippocratic oath: primum nil nocere Usually is true - less is more (tablets...)

CONCLUSIONS OR HOW TO ELIMINATE POLYPHARMACY AND REDUCE POLYPHARMACY? Seems to be very easy question in ideal population Unfortunately, physicians have their knowledge limits, patients will still sometimes prefer something else like it is recommended

CONCLUSIONS OR HOW TO ELIMINATE POLYPHARMACY AND REDUCE POLYPHARMACY? Seems to be very easy question in ideal population Unfortunately, physicians have their knowledge limits, patients will still sometimes prefer something else like it is recommended What could be expected in the future?

NEAR FUTURE OR NEXT DECADES? More omics in medicine (genomics, metabolomics, proteomics, etc.) not only in diagnostics, but also in therapeutic process Dramatic increase of research in biomedicine and translational medicine More and more personalized medicine to be applied

NEAR FUTURE OR NEXT DECADES? Wide use of e-health systems Implementation of arteficial intelligence into common clinical practice Elimination of polypragmasy, limitation of polypharmacy could be expected

Ďakujem Thank you Danke Dziekuje bardzo